Neuropeptide Y (NPY) is a 36 residue, amidated peptide. It is anatomically co-distributed and co-released with norepinephrine in and from sympathetic postganglionic neurons ([1], [2], [3], [4], [5], [6]). Stimulation of the sympathetic nervous system under physiological circumstances such as exercise ([7], [8]) or exposure to the cold ([9], [10]) promotes an elevation of both norepinephrine and NPY.
NPY is believed to act in the regulation of appetite control ([11], [12]) and vascular smooth muscle tone ([13], [14]) as well as regulation of blood pressure ([6], [15], [16], [17]). NPY also decreases cardiac contractility ([18], [19], [20], [21], [22]). Congestive heart failure and cardiogenic shock are associated with probable releases of NPY into the blood ([23], [24], [25]). Regulation of NPY levels may be beneficial to these disease states [26].
At the cellular level, neuropeptide Y binds to a G-protein coupled receptor ([27], [28], [29], [30]). Neuropeptide Y is involved in regulating eating behavior and is an extremely potent orixigenic agent ([11], [12], [31]). When administered intracerebroventricularly or injected into the hypothalamic paraventricular nucleus (PVN) it elicits eating in satiated rats ([32], [33], [34]) and intraventricular injection of antisera to NPY decreases eating ([11], [31]). It has been shown to stimulate appetite in a variety of species and at different stages of development ([12]). Other effects on energy metabolism include decreased thermogenesis, body temperature and uncoupling protein, and increased white fat storage and lipoprotein lipase activity ([9], [35], [36], [37], [38], [39]). NPY levels in the PVN increase upon fasting ([40], [41], [42], [43], [44]), before a scheduled meal ([31], [36], [40]), and in both streptozotocin-induced and spontaneous diabetes ([36], [45], [46], [47], [48], [49]). Also, NPY levels are increased in genetically obese and hyperphagic Zucker rats ([36], [50], [51]). Thus, a specific centrally acting antagonist for the appropriate NPY receptor subtype may be therapeutically useful for treating obesity and diabetes. Other disorders which might be targeted therapeutically include anxiety, hypertension, cocaine withdrawal, congestive heart failure, memory enhancement, cardiac and cerebral vasospasm, pheochromocytoma and ganglioneuroblastoma, and Huntington's, Alzheimer's and Parkinson's diseases ([26], [52]).
At least four receptor subtypes of the NPY family have been proposed based on pharmacological and physiological properties. The Y1 receptor is stimulated by NPY or PYY (peptide YY) and appears to be the major vascular receptor ([16], [53], [54], [55]). The Y2 receptor is stimulated by C-terminal fragments of NPY or PYY and is abundantly expressed both centrally and peripherally ([55], [56], [57], [58]). A third receptor (Y3) is exclusively responsive to NPY and is likely present in adrenal medulla, heart, and brain stem ([27], [59]). In addition, other subtypes of this receptor family are known to exist, based on pharmacological and physiological characterization ([60], [61], [62], [63]). The feeding behavior is stimulated potently by NPY, NPY.sub.2-36 and the Y1 agonist [Leu31, Pro34]NPY, but is not stimulated by the Y2 agonist NPY.sub.13-36 ([11], [64], [65], [66]). This pharmacology is not characteristic of the defined Y1, Y2 or Y3 receptors and can thus be attributed to a unique receptor, termed "atypical Y1" ([11], [65], [66]), that is responsible for evoking the feeding response. In addition, data indicate the existence of additional members of this receptor family including one subtype specific for peptide PP ([62], [63]), one with affinity for short C-terminal fragments of NPY which induce hypotension when administered systemically ([15], [17], [30], [67], [68]), and one associated with binding of NPY and PYY to brain sigma and phencyclidine binding sites ([61]).
The DNA encoding the Y 1 receptor has been cloned and shown to be a G protein coupled receptor ([53], [69], [70]). G-protein coupled receptors are well-known to share substantial sequence homology to each other (71). Recently, DNA encoding the Y4 receptor has been isolated using Y1 DNA probes [72]. In addition, DNA encoding the Y2 receptor has been isolated by expression cloning ([73], [74]). The cDNAs encoding these receptors are at least 45% identical at the DNA level and 30% at the protein level. Other NPY receptors have not been cloned.